Identifying the brain mechanisms that underlie drug addiction (a behaviorally defined disorder) requires neurobiological and behavioral tools of equal sophistication. This project will combine rigorous analytic techniques with a newly developed behavioral model that reveals an increased motivation to self-administer cocaine over time. The work will follow up on recent observations on two distinctly different neural systems. The first result is from a voltammetric analysis of nucleus accumbens slices from animals that have self-administered cocaine. The data demonstrate that autoreceptor function is down regulated during the 'incubation' or drug free phase, corresponding to a critical time period when the reinforcing efficacy of cocaine increases. Several voltammetric approaches (brain slices, in vivo anesthetized, freely moving animals) will be used to examine changes in the physiology of dopamine terminals at time points when rats are either tolerant or sensitized to the reinforcing effects of cocaine. Changes in the function of the dopamine system may contribute to the altered reinforcing efficacy of cocaine. A growing number of observations continue to confirm that gap junctions in brain change in response to drugs of abuse. Changes in gap junction proteins (connexins) will be examined after cocaine, heroin and speedbail self-administration across behaviorally relevant time points. Western blots and imunnohistochemical analysis will be used to assess regionally specific effects of connexin32 and connexin36 expression. This project will share tissue with subproject 0008 (Vrana) in which connexin RNAs and general proteomic screening will be performed.